from reportlab.lib.pagesizes import A4
from reportlab.lib import colors
from reportlab.lib.styles import getSampleStyleSheet, ParagraphStyle
from reportlab.platypus import (SimpleDocTemplate, Paragraph, Spacer, Table,
                                 TableStyle, HRFlowable)
from reportlab.lib.units import mm, cm
from reportlab.lib.enums import TA_CENTER, TA_LEFT, TA_JUSTIFY

OUTPUT = "/tmp/workspace/tissue-engineering/Tissue_Engineering_Restorative_Surgery.pdf"

doc = SimpleDocTemplate(
    OUTPUT,
    pagesize=A4,
    leftMargin=12*mm, rightMargin=12*mm,
    topMargin=10*mm, bottomMargin=10*mm,
)

W, H = A4

# ── Colour palette ──────────────────────────────────────────────────────────
NAVY   = colors.HexColor("#1a3561")
TEAL   = colors.HexColor("#0077b6")
LTBLUE = colors.HexColor("#caf0f8")
GOLD   = colors.HexColor("#f4a261")
LGREY  = colors.HexColor("#f0f4f8")
WHITE  = colors.white
BLACK  = colors.black
DKGREY = colors.HexColor("#333333")

# ── Styles ───────────────────────────────────────────────────────────────────
styles = getSampleStyleSheet()

TITLE = ParagraphStyle("TITLE", fontSize=14, textColor=WHITE,
                        fontName="Helvetica-Bold", alignment=TA_CENTER, spaceAfter=0)
SUBTITLE = ParagraphStyle("SUBTITLE", fontSize=8.5, textColor=LTBLUE,
                           fontName="Helvetica", alignment=TA_CENTER)
SH = ParagraphStyle("SH", fontSize=7.5, textColor=NAVY,
                     fontName="Helvetica-Bold", spaceBefore=3, spaceAfter=1)
BODY = ParagraphStyle("BODY", fontSize=6.4, textColor=DKGREY,
                       fontName="Helvetica", leading=8.5, spaceAfter=1,
                       alignment=TA_JUSTIFY)
BULLET = ParagraphStyle("BULLET", fontSize=6.3, textColor=DKGREY,
                         fontName="Helvetica", leading=8, leftIndent=8,
                         bulletIndent=2, spaceBefore=0)
THDG = ParagraphStyle("THDG", fontSize=6.5, textColor=WHITE,
                       fontName="Helvetica-Bold", alignment=TA_CENTER)
TCELL = ParagraphStyle("TCELL", fontSize=6.2, textColor=DKGREY,
                        fontName="Helvetica", alignment=TA_LEFT, leading=7.5)
TCELC = ParagraphStyle("TCELC", fontSize=6.2, textColor=DKGREY,
                        fontName="Helvetica", alignment=TA_CENTER, leading=7.5)
BOLD_CELL = ParagraphStyle("BOLD_CELL", fontSize=6.3, textColor=NAVY,
                            fontName="Helvetica-Bold", leading=7.5)
FOOTER = ParagraphStyle("FOOTER", fontSize=5.5, textColor=colors.HexColor("#888888"),
                         alignment=TA_CENTER, fontName="Helvetica-Oblique")
NOTE = ParagraphStyle("NOTE", fontSize=5.8, textColor=NAVY,
                       fontName="Helvetica-BoldOblique", alignment=TA_CENTER)

def bullet(text):
    return Paragraph(f"• {text}", BULLET)

def sh(text):
    return Paragraph(text, SH)

def body(text):
    return Paragraph(text, BODY)

# ── Helper: coloured section header bar ────────────────────────────────────
def sec_bar(text, bg=TEAL, fg=WHITE, fs=7.5):
    style = ParagraphStyle("sb", fontSize=fs, textColor=fg,
                            fontName="Helvetica-Bold", alignment=TA_LEFT)
    t = Table([[Paragraph(f"  {text}", style)]],
              colWidths=[W - 24*mm])
    t.setStyle(TableStyle([
        ("BACKGROUND", (0, 0), (-1, -1), bg),
        ("ROWBACKGROUNDS", (0, 0), (-1, -1), [bg]),
        ("TOPPADDING", (0, 0), (-1, -1), 3),
        ("BOTTOMPADDING", (0, 0), (-1, -1), 3),
        ("LEFTPADDING", (0, 0), (-1, -1), 4),
        ("BOX", (0, 0), (-1, -1), 0.4, bg),
    ]))
    return t

# ══════════════════════════════════════════════════════════════════════════════
story = []

# ── TITLE BANNER ─────────────────────────────────────────────────────────────
banner_data = [[Paragraph("TISSUE ENGINEERING IN RESTORATIVE SURGERY", TITLE)],
               [Paragraph("MD Exam Quick-Reference | Aug 2026  |  Sources: Sabiston 21e · Cummings ORL · Scott-Brown · Mulholland · PubMed 2023-26", SUBTITLE)]]
banner = Table(banner_data, colWidths=[W - 24*mm])
banner.setStyle(TableStyle([
    ("BACKGROUND", (0, 0), (-1, -1), NAVY),
    ("TOPPADDING", (0, 0), (-1, -1), 4),
    ("BOTTOMPADDING", (0, 0), (-1, -1), 3),
    ("LEFTPADDING", (0, 0), (-1, -1), 6),
]))
story.append(banner)
story.append(Spacer(1, 2*mm))

# ── ROW 1: Definition + Triad ─────────────────────────────────────────────
col1_w = 88*mm
col2_w = W - 24*mm - col1_w - 3*mm

# Left: definition + NSF
def_content = [
    sec_bar("DEFINITION & HISTORY"),
    Spacer(1, 1.5*mm),
    body("<b>NSF 1987 Definition:</b> \"Application of principles and methods of engineering and life sciences toward the development of biological substitutes to <b>restore, maintain, or improve</b> tissue function.\""),
    Spacer(1, 1*mm),
    body("<b>Key concept:</b> Instead of <i>transferring</i> tissue, tissue engineering <i>creates</i> new tissue using scaffolds, cells, and signals."),
    Spacer(1, 2*mm),
    sec_bar("THE TISSUE ENGINEERING TRIAD", bg=GOLD, fg=WHITE),
    Spacer(1, 1.5*mm),
]
triad_data = [
    [Paragraph("SCAFFOLD\n(Matrix)", THDG), Paragraph("CELLS\n(Seed)", THDG), Paragraph("SIGNALS\n(Growth Factors)", THDG)],
    [Paragraph("Biodegradable 3D framework\nCollagen, PCL, HA,\nPGA/PLA polymers,\nHydrogels, Ceramics", TCELL),
     Paragraph("Autologous > allogeneic\nKeratinocytes, Chondrocytes,\nOsteoblasts, MSCs,\niPSCs, Fibroblasts", TCELL),
     Paragraph("VEGF (angiogenesis)\nBMP-2/-7 (bone)\nbFGF (cartilage, skin)\nPDGF, TGF-β, IGF-1\nrhBMP-7 (clinical)", TCELL)],
]
triad = Table(triad_data, colWidths=[col1_w/3]*3)
triad.setStyle(TableStyle([
    ("BACKGROUND", (0, 0), (-1, 0), GOLD),
    ("BACKGROUND", (0, 1), (-1, -1), LGREY),
    ("GRID", (0, 0), (-1, -1), 0.4, colors.HexColor("#bbbbbb")),
    ("TOPPADDING", (0, 0), (-1, -1), 2), ("BOTTOMPADDING", (0, 0), (-1, -1), 2),
    ("LEFTPADDING", (0, 0), (-1, -1), 3), ("RIGHTPADDING", (0, 0), (-1, -1), 3),
    ("VALIGN", (0, 0), (-1, -1), "MIDDLE"),
]))
def_content.append(triad)

# Right: Mnemonics / key facts
right_content = [
    sec_bar("MNEMONIC: S-C-S"),
    Spacer(1,1.5*mm),
    body("<b>S</b>caffold  |  <b>C</b>ells  |  <b>S</b>ignals  → New Tissue"),
    Spacer(1,2*mm),
    sec_bar("SCAFFOLD PROPERTIES (MNEMONIC: BBBPP)", bg=colors.HexColor("#2d6a4f"), fg=WHITE),
    Spacer(1,1*mm),
    bullet("<b>B</b>iocompatible – no immune rejection"),
    bullet("<b>B</b>iodegradable – resorbs as tissue grows"),
    bullet("<b>B</b>iomechanical – mimics native stiffness"),
    bullet("<b>P</b>orous – allows cell ingrowth + vascularization"),
    bullet("<b>P</b>rintable – 3D/4D bioprinting compatible"),
    Spacer(1,2*mm),
    sec_bar("VASCULARIZATION CHALLENGE", bg=colors.HexColor("#6d4c41"), fg=WHITE),
    Spacer(1,1*mm),
    body("Key barrier for large defect reconstruction: tissues >200 µm need neovascularization. VEGF is the primary angiogenic driver."),
    Spacer(1,1.5*mm),
    body("<b>Solution strategies:</b> pre-vascularized scaffolds, VEGF-loaded microspheres, bioreactors, 4D printing"),
]

combined_top = Table(
    [[def_content, Spacer(1, 3*mm), right_content]],
    colWidths=[col1_w, 3*mm, col2_w]
)
combined_top.setStyle(TableStyle([
    ("VALIGN", (0, 0), (-1, -1), "TOP"),
    ("LEFTPADDING", (0, 0), (-1, -1), 0),
    ("RIGHTPADDING", (0, 0), (-1, -1), 0),
    ("TOPPADDING", (0, 0), (-1, -1), 0),
    ("BOTTOMPADDING", (0, 0), (-1, -1), 0),
]))
story.append(combined_top)
story.append(Spacer(1, 2*mm))

# ── MASTER TABLE: Clinical Applications ──────────────────────────────────────
story.append(sec_bar("CLINICAL APPLICATIONS IN RESTORATIVE SURGERY  (Master Table)", bg=NAVY))
story.append(Spacer(1, 1.5*mm))

tbl_full_w = W - 24*mm
cw = [28*mm, 35*mm, 40*mm, 38*mm, 40*mm]

headers = [Paragraph(h, THDG) for h in [
    "DOMAIN", "Product / Technique", "Scaffold / Material", "Cells / Signals", "Clinical Use / Notes"
]]

rows = [
    ["SKIN / WOUND",
     "Integra®\nBiobrane®\nApligraf®",
     "Bilayer: silicone + bovine collagen-GAG\nSilicone + nylon + porcine collagen\nType I collagen + fibroblasts",
     "Keratinocytes, Fibroblasts\nTGF-β, PDGF, VEGF",
     "Burns, chronic ulcers\nDiabetic/venous/pressure ulcers\nAlloDerm – breast reconstruction"],
    ["BONE",
     "rhBMP-7 / BMP-2\nBeta-TCP + HA scaffold\nGelMA hydrogels (2024)",
     "Type I collagen carrier\nβ-TCP + hydroxyapatite\nGelatin methacrylate",
     "MSCs, Osteoblasts\nBMP-2/-7, VEGF",
     "Alveolar cleft (6.5 yr follow-up)\nOsteoradionecrosis jaw\nSpinal fusion, long-bone defects"],
    ["CARTILAGE / EAR",
     "3D-printed PCL scaffold\nChondrocyte/HA hydrogel\nAutologous rib (gold standard)",
     "Polycaprolactone (PCL)\nHyaluronic acid hydrogel",
     "Chondrocytes, iPSCs\nbFGF, TGF-β",
     "Microtia reconstruction\nNasal/auricular repair\nHuman ear TE (China 2022)"],
    ["CARTILAGE / LARYNX",
     "Laryngeal TE (Scott-Brown)\nTracheal bioengineering",
     "Decellularized scaffold\nPorous ceramics",
     "MSCs, Chondrocytes\nVEGF for neovascularization",
     "Laryngeal stenosis\nTracheal replacement\nPhonation restoration"],
    ["NERVE",
     "Bioengineered nerve conduits\n(Hand Clin 2024)",
     "Biodegradable polymers\n(PGA, PCL, collagen)",
     "Schwann cells, NGF\nNT-3, BDNF",
     "Peripheral nerve gaps\nAlternative to autologous nerve graft\nBridge up to 30 mm"],
    ["TENDON / LIGAMENT",
     "3D-printed artificial tendon\n(JBMR 2024)",
     "PCL/PLA fibres\nElectrospun nanofibers",
     "Tenocytes, MSCs\nTGF-β, bFGF",
     "Rotator cuff, ACL repair\nHand tendon defects"],
    ["FETAL SURGERY",
     "MSC-based MMC repair\n(Mulholland 7e)",
     "Gelatin hydrogel\n(bFGF sustained release)",
     "Amniotic fluid MSCs\nPlacental MSCs",
     "Myelomeningocele coverage\nSpina bifida in-utero repair"],
    ["GYNECOLOGY",
     "Vaginal/uterine TE\n(Obstet Gynecol 2024)",
     "Decellularized ECM\nCollagen scaffolds",
     "Urothelial cells, MSCs",
     "Pelvic floor repair\nVaginal agenesis\nMullerian anomalies"],
]

# Build table rows
table_data = [headers]
for row in rows:
    formatted = []
    for i, cell in enumerate(row):
        if i == 0:
            formatted.append(Paragraph(cell, BOLD_CELL))
        else:
            formatted.append(Paragraph(cell, TCELL))
    table_data.append(formatted)

main_table = Table(table_data, colWidths=cw, repeatRows=1)
row_colors = [LGREY, WHITE] * 5

ts = TableStyle([
    ("BACKGROUND", (0, 0), (-1, 0), TEAL),
    ("ROWBACKGROUNDS", (0, 1), (-1, -1), [LGREY, WHITE]),
    ("GRID", (0, 0), (-1, -1), 0.3, colors.HexColor("#cccccc")),
    ("TOPPADDING", (0, 0), (-1, -1), 2),
    ("BOTTOMPADDING", (0, 0), (-1, -1), 2),
    ("LEFTPADDING", (0, 0), (-1, -1), 3),
    ("RIGHTPADDING", (0, 0), (-1, -1), 3),
    ("VALIGN", (0, 0), (-1, -1), "TOP"),
    ("FONTNAME", (0, 0), (-1, 0), "Helvetica-Bold"),
])
main_table.setStyle(ts)
story.append(main_table)
story.append(Spacer(1, 2*mm))

# ── ROW 3: Bottom 3-column layout ─────────────────────────────────────────
third = (W - 24*mm - 4*mm) / 3

# Col A: Current Updates 2024-26
col_a = [
    sec_bar("CURRENT UPDATES 2024-2026", bg=colors.HexColor("#7b2d8b"), fg=WHITE),
    Spacer(1, 1*mm),
    bullet("<b>4D/5D Bioprinting</b>: shape-memory scaffolds that respond to body temperature/pH"),
    bullet("<b>Organoids</b>: mini-organs for pre-clinical testing (Frontiers 2025)"),
    bullet("<b>iPSC-derived cells</b>: patient-specific, no rejection risk"),
    bullet("<b>Exosome therapy</b>: cell-free wound healing via MSC-derived exosomes"),
    bullet("<b>AI-designed scaffolds</b>: computer-optimised micro-architecture"),
    bullet("<b>Market (2025)</b>: $5.4B → $9.8B by 2030 (CAGR 12.8%)"),
    bullet("<b>Bone MSC + HA scaffold</b>: 40% HAp loading via electrospinning (2025)"),
]

# Col B: Classification of Skin Substitutes
col_b = [
    sec_bar("SKIN SUBSTITUTES CLASSIFICATION\n(Davison-Kotler 2018)", bg=colors.HexColor("#e76f51"), fg=WHITE),
    Spacer(1, 1*mm),
    body("<b>5 Criteria:</b> Cellularity | Layering | Region | Material | Permanence"),
    Spacer(1, 1*mm),
]
class_data = [
    [Paragraph("Product", THDG), Paragraph("Type", THDG), Paragraph("Use", THDG)],
    [Paragraph("Integra®", TCELL), Paragraph("Acellular bilayer\n(temp)", TCELL), Paragraph("Burns, wounds", TCELL)],
    [Paragraph("AlloDerm®", TCELL), Paragraph("Acellular dermal\n(temp)", TCELL), Paragraph("Breast recon.", TCELL)],
    [Paragraph("Apligraf®", TCELL), Paragraph("Cellular bilayer\n(temp)", TCELL), Paragraph("Chronic ulcers", TCELL)],
    [Paragraph("Biobrane®", TCELL), Paragraph("Acellular\nbilayer FT", TCELL), Paragraph("Burns", TCELL)],
    [Paragraph("Epicel®", TCELL), Paragraph("Cellular\nepidermal", TCELL), Paragraph("Massive burns", TCELL)],
]
class_t = Table(class_data, colWidths=[third/3]*3)
class_t.setStyle(TableStyle([
    ("BACKGROUND", (0, 0), (-1, 0), colors.HexColor("#e76f51")),
    ("ROWBACKGROUNDS", (0, 1), (-1, -1), [LGREY, WHITE]),
    ("GRID", (0, 0), (-1, -1), 0.3, colors.HexColor("#cccccc")),
    ("TOPPADDING", (0, 0), (-1, -1), 1.5), ("BOTTOMPADDING", (0, 0), (-1, -1), 1.5),
    ("LEFTPADDING", (0, 0), (-1, -1), 2), ("RIGHTPADDING", (0, 0), (-1, -1), 2),
    ("VALIGN", (0, 0), (-1, -1), "TOP"),
]))
col_b.append(class_t)

# Col C: Exam Points / Challenges
col_c = [
    sec_bar("HIGH-YIELD EXAM POINTS", bg=colors.HexColor("#1d7874"), fg=WHITE),
    Spacer(1, 1*mm),
    bullet("<b>Gold standard</b> skin: split-thickness autograft"),
    bullet("<b>Integra</b>: bovine collagen + GAG + silicone; remove outer layer at 2-3 wks"),
    bullet("<b>AlloDerm</b>: acellular cadaveric dermis; breast recon"),
    bullet("<b>rhBMP-7</b>: used in alveolar cleft repair (6.5 yr data)"),
    bullet("<b>Vascularization</b> = #1 barrier to large construct viability"),
    bullet("<b>MMC fetal repair</b>: amniotic fluid MSCs + gelatin-bFGF"),
    bullet("<b>Ear TE</b>: PCL scaffold + chondrocyte/HA; preclinical only in USA"),
    Spacer(1, 1.5*mm),
    sec_bar("CHALLENGES", bg=colors.HexColor("#c62828"), fg=WHITE),
    Spacer(1, 1*mm),
    bullet("Regulatory barriers (FDA pathway)"),
    bullet("High manufacturing cost"),
    bullet("Limited vascularization of thick constructs"),
    bullet("Cell sourcing & immunogenicity"),
    bullet("Long-term durability data lacking"),
]

bottom_row = Table(
    [[col_a, Spacer(1, 2*mm), col_b, Spacer(1, 2*mm), col_c]],
    colWidths=[third, 2*mm, third, 2*mm, third]
)
bottom_row.setStyle(TableStyle([
    ("VALIGN", (0, 0), (-1, -1), "TOP"),
    ("LEFTPADDING", (0, 0), (-1, -1), 0),
    ("RIGHTPADDING", (0, 0), (-1, -1), 0),
    ("TOPPADDING", (0, 0), (-1, -1), 0),
    ("BOTTOMPADDING", (0, 0), (-1, -1), 0),
]))
story.append(bottom_row)
story.append(Spacer(1, 2*mm))
story.append(HRFlowable(width="100%", thickness=0.5, color=TEAL))
story.append(Spacer(1, 1*mm))
story.append(Paragraph(
    "References: Sabiston Textbook of Surgery 21e (Ch.23) · Cummings Otolaryngology HNS (Ch.195) · Scott-Brown's ORL HNS Vol.1 · Mulholland & Greenfield's Surgery 7e · "
    "Downer et al. Bioengineering 2023 (PMID 38135969) · Wong & Chung, Hand Clin 2024 (PMID 38972682) · Alhaskawi et al. JBMR 2024 (PMID 38359172) · Balough & Moalli, Obstet Gynecol 2024 (PMID 38663014)",
    FOOTER))

# ── BUILD ────────────────────────────────────────────────────────────────────
doc.build(story)
print("PDF generated:", OUTPUT)